Enhanced expression of endothelial nitric oxide synthase and caveolin‐1 in human cirrhosis

Yokomori, Hiroaki; Oda, Masaya; Ogi, Mariko; Sakai, Kaoru; Ishii, Hiromasa

doi:10.1034/j.1600-0676.2002.01588.x

Cited by 55 publications

(42 citation statements)

References 33 publications

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“…Caveolin-1 is a protein found in fenestrations [20]. Its upregulation has been reported in cirrhosis of the liver [21]. Our finding of increased staining for the Masson's trichrome reagent is consistent with deposition of extravascular matrix.…”

Section: Discussionsupporting

confidence: 83%

Alterations in liver sinusoidal endothelium in a baboon model of type 1 diabetes

et al. 2007

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Aims/hypothesis Diabetes mellitus is associated with extensive vascular pathology, yet little is known about its longterm effects on liver sinusoidal endothelial cells (LSECs).Potential diabetic changes in LSECs are important because of the role played by fenestrations in the LSECs in hepatic disposition of lipoproteins. Materials and methods Surgical liver biopsies for electron microscopy and immunohistochemistry were obtained from baboons with long-standing streptozotocin-induced, insulin-treated diabetes mellitus and compared with those from age-matched control animals. Results There was an increase in the thickness of LSECs (170±17 vs 123±10 nm, p<0.01). Fenestrations in LSECs, as determined by overall porosity, were markedly reduced (1.4±0.1% vs 2.6±0.2%, p<0.01). Increased numbers of stellate cells were seen on electron microscopy, and this finding was corroborated by increased smooth muscle actin expression. Diabetes mellitus was also associated with increased endothelial production of von Willebrand factor and caveolin-1. Conclusions/interpretation Diabetes mellitus in the nonhuman primate is associated with marked changes in LSECs, including a reduction in fenestrations. Such changes provide an additional and novel mechanism for impaired hepatic lipoprotein clearance and post-prandial hyperlipidaemia in diabetes mellitus.

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Section: Discussionsupporting

confidence: 83%

Alterations in liver sinusoidal endothelium in a baboon model of type 1 diabetes

et al. 2007

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“…26 Even though the expression of endothelial NO synthases (eNOS) is increased in livers with cirrhosis, the activity of eNOS is reduced by promoting caveolin-eNOS binding, and NO production is impaired. 27 In our study, using the fluorescent dye, we were able to directly visualize the release of NO in the liver. Both basal NO production, and the production of NO induced by tumor cell arrest were significantly reduced in the livers with cirrhosis.…”

Section: Discussionmentioning

confidence: 99%

Impact of cirrhosis on the development of experimental hepatic metastases by B16F1 melanoma cells in C57BL/6 mice

et al. 2004

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Metastases rarely occur in human livers with cirrhosis in clinical studies. We postulated that this phenomenon would also occur in experimental cirrhosis. Cirrhosis was established in C57BL/6 mice by carbon tetrachloride (CCl 4 ) gastrogavage. B16F1 melanoma cells were injected into the mesenteric vein to induce hepatic metastases. Contrary to our postulate, there was greater than 4-fold increase in metastasis in animals with cirrhosis compared to controls. Intravital videomicroscopy showed that the hepatic sinusoids were narrower and more tumor cells were retained in the terminal portal vein ( T he liver is a common site of metastatic tumor growth. Interestingly, the liver with cirrhosis has been reported to inhibit metastasis. 1 In clinical studies, colorectal cancers rarely metastasize to livers with cirrhosis. 2,3 Autopsy studies have shown that the rate of metastasis to such livers is lower than that to normal livers. 4,5 However, the mechanisms responsible for this result are not clear. Vanbockrijck and Kloppel suggested that the lower incidence of metastasis is due to a shorter life expectancy of patients with cirrhosis. 6 Seymour and Charnley considered that venovenous shunting in cirrhosis may prevent tumor cells from reaching the liver, and that changes in the architecture of cirrhotic sinusoids may reduce metastasis. 5 The activation of Kupffer cells in cirrhosis may also inhibit the formation of hepatic metastases. 7 Based on previous studies, the fate of metastatic cells in the liver is determined by the expression of hepatic microvasculature adhesion molecules and the release of endothelial-derived nitric oxide (NO). Specifically, the expression of inducible vascular adhesion molecules can cause tumor cell arrest in terminal portal vein (TPV) and increase metastasis. 8 Alternatively, tumor cell arrest in hepatic sinusoids can induce endothelial and hepatic NO release, causing tumor cell apoptosis and inhibiting metastasis. 9,10 We predicted these mechanisms would apply in a cirrhotic model. To examine this possibility, we established cirrhosis in C57BL/6 mice, using carbon tetrachloride (CCl 4 ) gastrogavage. Liver metastasis was induced by injecting B16F1 melanoma cells into the portal venous system. Surprisingly, we found a significant increase in metastasis of B16F1 melanoma cells in animals with cirrhosis. Our studies demonstrated that alterations

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“…More recently in cholestatic models of disease, the upregulation of sinusoidal caveolin-1 and a decrease in eNOS activity is seen (Shah et al 2001). Most importantly, elevated expression of caveolin-1 has been found in patients with hepatocellular carcinoma and hepatitis C related cirrhosis suggesting that the upregulation of caveolin-1 may be contribute to endothelial dysfunction in the liver (Yokomori et al 2002(Yokomori et al , 2003.…”

Section: Regulation Of No Production By Protein-protein Interactions mentioning

confidence: 99%

Regulation of endothelial derived nitric oxide in health and disease

Sessa

2005

Mem. Inst. Oswaldo Cruz

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In the past decade the importance of the vascular endothelium as a multifunctional regulator of vascular smooth muscle physiology and pathophysiology has been appreciated. Indeed, the endothelium responds to hemodynamic stimuli (pressure, shear stress, and wall strain) and locally manufactured mediators (such as bradykinin, prostaglandins, and angiotensin) and in turn can release factors that can influence the adhesion and aggregation of circulating cells to the endothelium and the tone of vascular smooth muscle. In many diseases, including atherosclerosis, diabetes or cirrhosis endothelial dysfunction manifested as an impairment nitric oxide (NO) production or bioactivity may be an early hallmark of disease and a treatable entity. In this chapter, the importance of NO as a mediator of vascular function and potential mechanisms of endothelial NO synthase (eNOS) activation in disease will be discussed. Regulation of vascular tone by endogenous NOeNOS is the NOS isoform responsible for producing the classical endothelium-derived relaxing factor as originally described by (Furchgott & Zawadski 1981). Evidence for the importance of eNOS derived NO in the regulation of vascular tone is based on experiments in animals and in humans demonstrating that L-arginine based inhibitors of NOS increase blood or perfusion pressure and vascular resistance and reduce blood flow in vivo and in vitro. More recently, this has been unequivocally confirmed using mice with targeted disruption of the eNOS gene locus. eNOS knockout mice (-/-) are mildly hypertensive relative to wild-type littermate control mice (+/+) of the same generation. Importantly, the pressor effect of nitro-L-arginine, a NOS inhibi- tor, is attenuated in the -/-mice and endothelium-dependent relaxation in response to acetylcholine is abrogated in isolated vessels (Huang et al. 1995, Shesely et al. 1996. This fundamental finding is direct "proof of-principal" for the major contribution of NO in vasomotor control in large blood vessels. Physiological activation of eNOS and NO releaseTypically, endothelial cells release NO in response to autacoids that mobilize intracellular calcium such as thrombin, VEGF or ADP. The proposed mechanism for eNOS activation is that the released calcium will bind to calmodulin (CaM) and the calcium/CaM complex will bind to the CaM site in the enzyme promote NO synthesis. However, the most physiological agonist for NO release is fluid shear stress. Shear stress in vitro or shear rate in vivo, is the tangential vector of force elicited by the flow of blood over the endothelial cell surface. Exposure of endothelial cells to shear stress results in a burst of NO release, followed by a sustained phase. In vivo, increasing shear rate due to high blood flow will cause flow dependent dilations of certain vascular beds while decreasing shear rate will promote vasoconstriction. Shear induced NO release in vitro and flow-dependent vasodilation in vivo can be blocked with NOS inhibitors. Interestingly, shearinduced NO release appears to "independen...

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Enhanced expression of endothelial nitric oxide synthase and caveolin‐1 in human cirrhosis

Abstract: In cirrhotic human liver, marked increase of caveolin-1 in perisinusoidal cells may promote caveolin-eNOS binding and reduce the activity of eNOS despite an increased eNOS expression, leading to impaired NO production and increased hepatic microvascular tone.

Cited by 55 publications

References 33 publications

Alterations in liver sinusoidal endothelium in a baboon model of type 1 diabetes

Alterations in liver sinusoidal endothelium in a baboon model of type 1 diabetes

Impact of cirrhosis on the development of experimental hepatic metastases by B16F1 melanoma cells in C57BL/6 mice

Regulation of endothelial derived nitric oxide in health and disease

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